Tissue adhesives have many potential medical applications, including topical wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.
Protein-based tissue adhesives using albumin or gelatin are known. For example, Wilkie et al. (U.S. Patent Application Publication No. 2002/0022588) and Tammishetti et al. (WO 99/66964) describe tissue adhesives formed by crosslinking albumin with a carbodiimide. The addition of a polyamine, specifically, poly(lysine) or chitosan, or a polycarboxylate, specifically, citric acid or poly(acrylic acid), to increase the rate of crosslinking is also described in those disclosures. However, for use as a tissue adhesive for in vivo applications, such as intestinal anastomosis, adhesives with lower toxicity and enhanced adhesive strength are needed. The use of carbodiimides in the adhesive composition causes some toxicity problems. The toxicity problem is exacerbated by the use of a toxic polyamine such as poly(lysine). Chitosan is not soluble enough to be effective in increasing the adhesive properties of the adhesive.
Otani et al. (J. Biomed. Mater. Res. 31:157-166 (1996); and Biomaterials 17:1387-1391 (1996)) describe a tissue adhesive prepared by crosslinking gelatin and poly(L-glutamic acid) with a water-soluble carbodiimide. Although the adhesive is less toxic than the albumin-poly(lysine) adhesive described above, it lacks adhesive strength.
Therefore in the continuing search for new tissue adhesives for in vivo applications, such as intestinal anastomosis, the problem to be solved is to provide a protein-based tissue adhesive with lower toxicity and higher adhesive strength than those currently available.
Applicants have addressed the stated problem by discovering a tissue adhesive formed by crosslinking albumin and/or gelatin with certain polyamines and/or certain polycarboxylates using a water-soluble carbodiimide. The polyamines and polycarboxylates of the invention have low toxicity and provide a tissue adhesive with improved adhesive strength. Additionally, the polyamines and polycarboxylates of the invention permit the use of a lower carbodiimide concentration than can be used in the absence of the polyamines or polycarboxylates or in the presence of the polyamines or polycarboxylates known in the art, thereby further reducing the toxicity of the adhesive.